Background, aims: In a previous cross‐sectional study, the relevant rôle of time in reducing gingival overgrowth (GO) in heart‐transplanted patients undergoing Cyclosporin A (CsA) therapy was hypothesized to explain the inverse relationship between GO and months since the graft.Methods: In the present study, the relationship between GO and time was investigated prospectively in a group of 21 heart transplanted patients who have been regularly followed up to 48 months.Results: 6 months after beginning CsA therapy (1st appointment), 7 out of 21 patients (33%) had clinical GO as confirmed by a hyperplastic index (HI) >30. There was no significant difference between these values with respect to those detected during the 2nd appointment at 9 months. At this time, all patients underwent a regular oral hygiene program. Gingival and plaque indices significantly decreased at the 3rd appointment (12 months) both in the group of responders and in the group of non‐responders and remained significantly unchanged with time; HI significantly decreased with time only in the group of responders, the decrease becoming significant 36 months after heart transplantation. As a consequence, the number of responders decreased from 7 at the 1st appointment to 5 after 12 months, 4 after 24 months, 2 after 36 months following heart transplantation.Conclusion: The results suggest that GO necessarily develops in responders within 6 months from heart transplantation and in most subjects may be a time‐related side‐effect probably due to a progressive reduction in the sensitivity of the periodontum to CsA.